All are affected in graft versus host reaction

Ref Robbins 9/e p236 REJECTION OF TRANSPLANTS The major barrier to transplantation of organs from one individual to another of the same species (called allografts) is immunologic rejection of the transplanted tissue. Rejec- tion is a complex phenomenon involving both cell- and antibody-mediated reactions that destroy the graft. The key to successful transplantation has been the development of therapies that prevent or minimize rejection. Discussed next is how grafts are recognized as foreign and how they are rejected. Immune Recognition of Allografts Rejection of allografts is a response mainly to MHC molecules, which are so polymorphic that most individuals in an outbred population differ in at least some of the MHC molecules they express (except, of course, for identical twins). There are two main mechanisms by which the host immune system recognizes and responds to the MHC mol- ecules on the graft (Fig. 4-23): * Direct recognition. Host T cells directly recognize the allo- geneic (foreign) MHC molecules that are expressed on graft cells. Direct recognition of foreign MHC seems to violate the rule of MHC restriction, which states that in every individual, all of the T cells are educated to recog- nize foreign antigens displayed by only that individual's MHC molecules. It is postulated that allogeneic MHC molecules (with any bound peptides) structurally mimic self MHC and foreign peptide, and so direct recognition of the allogeneic MHC is essentially an immunologic cross-reaction. Because DCs in the graft express high levels of MHC as well as costimulatory molecules, they are believed to be the major culprits contributing to direct recognition. The most impoant consequence of direct recognition is the activation of host CD8+ T cells that recognize class I MHC (HLA-A, -B) molecules in the graft. These T cells differentiate into CTLs, which kill the cells in the graft. Host CD4+ helper T cells may be trig- gered into proliferation and cytokine production by rec- ognition of donor class II MHC (HLA-D) molecules and drive an inflammatory response. Indirect recognition. In this pathway, host CD4+ T cells recognize donor MHC molecules after these molecules are picked up, processed, and presented by the host's own APCs. This sequence is similar to the physiologic processing and presentation of other foreign (e.g., microbial) antigens. The activated CD4+ T cells then recognize APCs displaying graft antigens and secrete cytokines that induce inflammation and damage the graft. The indirect pathway is also involved in the pro- duction of antibodies against graft alloantigens; if these antigens are proteins, they are picked up by host B cells, and peptides are presented to helper T cells, which then stimulate antibody responses. Effector Mechanisms of Graft Rejection Both T cells and antibodies reactive with the graft are involved in the rejection of most solid-organ allografts (Fig. 4-23). T Cell-Mediated Rejection CTLs kill cells in the grafted tissue, causing parenchymal and endothelial cell death (the latter resulting in thrombo- sis and graft ischemia). Cytokine-secreting CD4+ T cells trigger inflammatory reactions resembling DTH in the tissues and blood vessels, with local accumulation of mononuclear cells (lymphocytes and macrophages). Acti- vated microphages can injure graft cells and vasculature. The microvascular injury also results in tissue ischemia, which contributes to graft destruction. Antibody-Mediated Rejection Although T cells are of paramount impoance in allograft rejection, antibodies also mediate some forms of rejection. Alloantibodies directed against graft MHC molecules and other alloantigens bind to the graft endothelium and cause vascular injury through complement activation and recruit- ment of leukocytes. Superimposed on the resulting endo- thelial damage and dysfunction is thrombosis, adding fuher ischemic insult to the injury. Hyperacute rejection is a special form of rejection occur- ring if pre-formed anti-donor antibodies are present in the circulation of the host before transplantation. This may happen in multiparous women who have anti-HLA anti- bodies against paternal antigens encountered during preg- nancy, or in individuals exposed to foreign HLA (on platelets or leukocytes) from previous blood transfusions. Obviously, such antibodies also may be present in a patient who has previously rejected an organ transplant. Subse- quent transplantation in such patients will result in imme- diate rejection (within minutes to hours) because the MORPHOLOGY On the basis of the time course and morphology of rejection reactions, they have been classified as hyperacute, acute, and chronic (Fig. 4-24). This classification is helpful for under- standing the mechanism of rejection, because each pattern is caused by a different type of dominant immunologic reaction. The morphology of these patterns is described in the context of renal transplants; however, similar changes are encoun- tered in other vascularized organ transplants. Hyperacute Rejection Hyperacute rejection occurs within minutes to a few hours after transplantation in a presensitized host and typically is recognized by the surgeon just after the vascular anastomosis is completed. In contrast with a nonrejecting kidney graft, which regains a normal pink color and tissue turgor and promptly excretes urine, a hyperacutely rejecting kidney rapidly becomes cyanotic, mottled, and flaccid and may excrete only a few drops of bloody fluid. The histologic picture is characterized by widespread acute aeritis and aeriolitis, vessel thrombosis, and ischemic necrosis, all resulting from the binding of preformed antibodies to graft endothelium. Viually all aerioles and aeries exhibit char- acteristic acute fibrinoid necrosis of their walls, with narrow- ing or complete occlusion of the lumens by precipitated fibrin and cellular debris (Fig. 4-24, A). circulating antibodies rapidly bind to the endothelium of the grafted organ, with resultant complement activation and vascular thrombosis. With the current practice of screening potential recipients for pre-formed anti-HLA antibodies and cross-matching (testing recipients for the presence of antibodies directed against the donor's lym- phocytes), hyperacute rejection occurs in less than 0.4% of transplant recipients. Acute Rejection Acute rejection may occur within days to weeks of transplan- tation in a nonimmunosuppressed host or may appear months or even years later, even in the presence of adequate immunosuppression. Acute rejection is caused by both cel- lular and humoral immune mechanisms, and in any one patient, one or the other may predominate, or both may be present. On histologic examination, cellular rejection is marked by an interstitial mononuclear cell infiltrate with asso- ciated edema and parenchymal injury, whereas humoral rejection is associated with vasculitis. Acute cellular rejection most commonly is seen within the first months after transplantation and typically is accom- panied by clinical signs of renal failure. Histologic examination usually shows extensive interstitial CD4+ and CD8+ T cell infiltration with edema and mild interstitial hemorrhage (Fig. 4-24, B). Glomerular and peritubular capillaries contain large numbers of mononuclear cells, which also may invade the tubules, leading to focal tubular necrosis. In addition to tubular injury, CD8+ T cells also may injure the endothelium, causing an endothelitis. Cyclosporine (a widely used immu- nosuppressive agent) is also nephrotoxic and induces so- called aeriolar hyaline deposits. Renal biopsy is used to distinguish rejection from drug toxicity. Accurate recogni- tion of cellular rejection is impoant, because patients typi- cally respond promptly to increased immunosuppressive therapy. Acute humoral rejection (rejection vasculitis) caused by antidonor antibodies also may paicipate in acute graft rejection. The histologic lesions may take the form of necro- tizing vasculitis with endothelial cell necrosis; neutrophilic infiltration; deposition of antibody, complement, and fibrin; and thrombosis. Such lesions may be associated with isch- emic necrosis of the renal parenchyma. Somewhat older subacute lesions are characterized by marked thickening of the intima by proliferating fibroblasts, myocytes, and foamy macrophages (Fig. 4-24, C). The resultant narrowing of the aerioles may cause infarction or renal coical atrophy. The proliferative vascular lesions mimic aeriosclerotic thickening and are believed to be caused by cytokines that stimulate proliferation of vascular smooth muscle cells. Local deposi- tion of complement breakdown products (specifically C4d) is used to detect antibody-mediated rejection of kidney allografts. Chronic Rejection Patients present with chronic rejection late after transplanta- tion (months to years) with a progressive rise in serum cre- atinine levels (an index of renal function) over a period of 4 to 6 months. Chronic rejection is dominated by vascular changes, interstitial fibrosis, and loss of renal parenchyma; there are typically only mild or no ongoing cellular parenchy- mal infiltrates. The vascular changes occur predominantly in the aeries and aerioles, which exhibit intimal smooth muscle cell proliferation and extracellular matrix synthesis (Fig. 4-24, D). These lesions ultimately compromise vascular perfusion and result in renal ischemia manifested by loss or hyalinization of glomeruli, interstitial fibrosis, and tubular atrophy. The vascular lesion may be caused by cytokines released by activated T cells that act on the cells of the vas- cular wall, and it may be the end stage of the proliferative aeritis described earlier.